Solutions

Chapter 2

Solutions

CONTENTS
 Introduction  Colligative Properties
 Types of solutions Lowering of Vapor pressure
 Solubility Elevation of Boiling point
 Types of solvents Depression of Freezing point

 Concentration Expressions Osmotic Pressure

 Ideal solutions and Raoults Law  Molecular weight Determination

 Real Solutions  Factors affecting the solubility of

Positive deviation from Raoult’s Law solids in liquids

Negative deviation from Raoult’s Law  Factors affecting the solubility of

 Properties of Solutions gases in liquids

 Partition Co-efficient

Solution:

A true solution is defined as a mixture of two or more components that form a homogeneous
molecular dispersion, in other words, a one-phase system.

Phase:

The term phase is defined as a distinct homogeneous part of a system separated by definite
boundaries from other parts of the system.

Solvent:

The component that determines the phase of the solution is termed the solvent and usually
constitutes the largest proportion of the system.
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Solute:

The other components are termed solutes, and these are dispersed as molecules or ions
throughout the solvent, i.e. they are said to be dissolved in the solvent.

Dissolution:

The transfer of molecules or ions from a solid state into solution is known as dissolution.

Solubility:

The United States Pharmacopeia (USP) describes the solubility of drugs as parts of solvent
required for one part solute.

Solubility is defined in quantitative terms as the concentration of solute in a saturated solution at

a certain temperature.

It can be defined in qualitative way as the spontaneous interaction of two or more substances to
form a homogeneous molecular dispersion.

Types of solutions:

Saturated Solution:

A saturated solution is one in which the solute in solution is in equilibrium with the solid phase.

Unsaturated Solution:

An unsaturated or sub-saturated solution is one containing the dissolved solute in a concentration

below that necessary for complete saturation at a definite temperature.

Supersaturated Solution:

A supersaturated solution is one that contains more of the dissolved solute than it would
normally contain at a definite temperature, were the un-dissolved solute present.
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Table 1.1 Types of Solutions

Solute Solvent Example

Gas Gas Air

Liquid Gas Water in oxygen
Solid Gas Iodine vapor in air
Gas Liquid Carbonated water
Liquid Liquid Alcohol in water
Solid Liquid Aqueous sodium chloride solution
Gas Solid Hydrogen in palladium
Liquid Solid Mineral oil in paraffin
Solid Solid Gold—silver mixture, mixture of alums

Table 1.2 Solubility Definitions in the United States Pharmacopeia

Description Forms Parts of Solvent Required for One Solubility Solubility

Part of Solute Range Assigned
(Solubility
Definition) (mg/mL) (mg/mL)

Very soluble (VS) <1 >1000 1000

Freely soluble (FS) From 1 to 10 100–1000 100
Soluble From 10 to 30 33–100 33
Sparingly From 30 to 100 10–33 10
soluble(SPS)
Slightly soluble (SS) From 100 to 1000 1–10 1
Very slightly soluble From 1000 to10,000 0.1–1 0.1
(VSS)
Practically insoluble >10,000 <0.1 0.01
(PI)
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Polar Solvents:

The solubility of a drug is due in large measure to the polarity of the solvent, that is, to its dipole
moment. Polar solvents dissolve ionic solutes and other polar substances. Accordingly, water
mixes in all proportions with alcohol and dissolves sugars and other polyhydroxy compounds.
Hildebrand showed, however, that a consideration of dipole moments alone is not adequate to
explain the solubility of polar substances in water. The ability of the solute to form hydrogen
bonds is a far more significant factor than is the polarity as reflected in a high dipole moment.
Water dissolves phenols, alcohols, aldehydes, ketones, amines, and other oxygen- and nitrogen-
containing compounds that can form hydrogen bonds with water

In addition to the factors already enumerated, the solubility of a substance also depends on
structural features such as the ratio of the polar to the nonpolar groups of the molecule. As the
length of a nonpolar chain of an aliphatic alcohol increases, the solubility of the compound in
water decreases. Straight-chain monohydroxy alcohols, aldehydes, ketones, and acids with more
than four or five carbons cannot enter into the hydrogen-bonded structure of water and hence are
only slightly soluble. When additional polar groups are present in the molecule, as found in
propylene glycol, glycerin, and tartaric acid, water solubility increases greatly
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Figure 1.1 Hydrogen bonding between polar substances and water

Non-Polar Solvents:

The solvent action of nonpolar liquids, such as the hydrocarbons, differs from that of polar
substances. Nonpolar solvents are unable to reduce the attraction between the ions of strong and
weak electrolytes because of the solvents' low dielectric constants. Nor can the solvents break
covalent bonds and ionize weak electrolytes, because they belong to the group known as aprotic
solvents, and they cannot form hydrogen bridges with nonelectrolytes. Hence, ionic and polar
solutes are not soluble or are only slightly soluble in nonpolar solvents. Nonpolar compounds,
however, can dissolve nonpolar solutes through induced dipole interactions. The solute
molecules are kept in solution by the weak van der Waals– London type of forces. Thus, oils
and fats dissolve in carbon tetrachloride, benzene, and mineral oil. Alkaloidal bases and fatty
acids also dissolve in nonpolar solvents.
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Semi-Polar Solvents:

Semipolar solvents, such as ketones and alcohols, can induce a certain degree of polarity in
nonpolar solvent molecules, so that, for example, benzene, which is readily polarizable, becomes
soluble in alcohol. In fact, semipolar compounds can act as intermediate solvents to bring about
miscibility of polar and nonpolar liquids. Accordingly, acetone increases the solubility of ether in
water. Loran and Guth studied the intermediate solvent action of alcohol on water–castor oil
mixtures. Propylene glycol has been shown to increase the mutual solubility of water and
peppermint oil.

Concentration Expressions:

Molarity:

This is the number of moles of solute contained in 1 dm3 (or,1 litre) of solution. Thus, solutions
of equal molarity contain the same number of solute molecules in a given volume of solution.
The unit of molarity is mol/L.

Molality:

This is the number of moles of solute per kg of the solvent, i.e. its SI unit is mol/kg.

Mole Fraction:

This is often used in theoretical considerations and is defined as the number of moles of solute
divided by the total number of moles of solute and solvent, i.e.: mole fraction of solute.

X1=n1/n1+n2 (2.1)

where n1 and n2 are the numbers of moles of solute and solvent, respectively.

Normality:

Gram equivalent weights of solute in 1 liter of solution.

Equivalent Weight= (2.2)

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Percentage Solutions:

%w/v:

Grams of solute in 100 mL of solution

%w/w:

Grams of solute in 100 g of solution

%v/v:

Milliliters of solute in 100 mL of solution.

Parts per Million (ppm):

Parts of solute per million parts of solution.

Example 2.1

An aqueous solution of exsiccated ferrous sulfate was prepared by adding 41.50 g of FeSO4 to
enough water to make 1000 mL of solution at 18°C. The density of the solution is 1.0375 and the
molecular weight of FeSO4 is 151.9. Calculate (a) the molarity; (b) the molality; (c) the mole
fraction of FeSO4, the mole fraction of water, and the mole percent of the two constituents; and
(d) the percentage by weight of FeSO4.
Solution:
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Vapor Pressure:

Although solids and liquids are condensed systems with cohering molecules, some of the surface
molecules in these systems will occasionally acquire sufficient energy to overcome the attractive
forces exerted by adjacent molecules. They can therefore escape from the surface to form a
vapor phase. If temperature is maintained constant, equilibrium will eventually be established
between the vapor and the condensed phases, and the pressure exerted by the vapour at
equilibrium is referred to as the vapor pressure of the substance. It will also depend on the
relative strengths of the attractive forces between adjacent solvent molecules on the one hand and
between solute and solvent molecules on the other. Therefore, as the intermolecular forces
between solid solutes and liquid solvents tend to be relatively strong, such solute molecules do
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not generally escape from the surface of a solution and do not contribute to the vapor pressure.
In other words, the solute is generally nonvolatile and the vapor pressure arises solely from the
dynamic equilibrium that is set up between the rates of evaporation and condensation of solvent
molecules contained in the solution. In a mixture of miscible liquids, i.e. a liquid in liquid
solution, the molecules of both components are likely to evaporate and contribute to the overall
vapor pressure exerted by the solution.

Ideal Solutions:

It is convenient to define an ideal solution as one in which there is no change in the properties of
the components, other than dilution, when they are mixed to form the solution. No heat is
evolved or absorbed during the mixing process, and the final volume of the solution represents
an additive property of the individual constituents. Stated another way, no shrinkage or
expansion occurs when the substances are mixed.

Mixing substances with similar properties forms ideal solutions. For example, when 100 mL of
methanol is mixed with 100 mL of ethanol, the final volume of the solution is 200 mL, and no
heat is evolved or absorbed. The solution is nearly ideal. Mixtures of benzene + toluene, n-
hexane + n-heptane and ethyl bromide + ethyl iodide are commonly mentioned systems that
exhibit ideal behavior. When 100 mL of sulfuric acid is combined with 100 mL of water,
however, the volume of the solution is about 180 mL at room temperature, and the mixing is
attended by a considerable evolution of heat; the solution is said to be non-ideal, or real.

Ideal Solutions and Raoult's Law:

The vapor pressure of a solution is a particularly important property because it serves as a

quantitative expression of escaping tendency. In 1887, Raoult recognized that, in an ideal
solution, the partial vapor pressure of each volatile constituent is equal to the vapor pressure of
the pure constituent multiplied by its mole fraction in the solution. Thus, for two constituents A
and B,

PA=PAoXA (2.3)

PB=PBoXB (2.4)
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Where ‘p1’ and ‘p2’ are the partial vapor pressures of the constituents over the solution when the
mole fraction concentrations are X1 and X2, respectively. The vapor pressures of the pure
components are p1° and p2°, respectively. Thus the total vapor pressure exerted by such a binary
system is given by;

P = PA+PB = PAoXA + PBoXB (2.5)

For example, if the vapor pressure of ethylene chloride in the pure state is 236 mm Hg at 50°C,
then in a solution consisting of a mole fraction of 0.4 ethylene chloride and 0.6 benzene, the
partial vapor pressure of ethylene chloride is 40% of 236 mm, or 94.4 mm. Thus, in an ideal
solution, when liquid A is mixed with liquid B, the vapor pressure of A is reduced by dilution
with B in a manner depending on the mole fractions of A and B present in the final solution. This
will diminish the escaping tendency of each constituent, leading to a reduction in the rate of
escape of the molecules of A and B from the surface of the liquid.

Fig. 2.2 Vapor pressure composition curve for an ideal binary solution
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Real or non-ideal solutions:

The majority of real solutions do not exhibit ideal behavior because solute-solute, solute-solvent
and solvent-solvent forces of interaction are unequal. These inequalities alter the effective
concentration of each component so that it cannot be represented by a normal expression of
concentration, such as the mole fraction term x. Consequently, deviations from Raoult's law are
often exhibited by real solutions, and the previous equations are not obeyed in such cases. These
equations can be modified, however, by substituting each concentration term (x) by a measure of
the effective concentration; this is provided by the so-called activity (or thermodynamic activity),
‘a’.

Thus equation is converted into

PA=PAoaA (2.6)

PB=PBoaB (2.7)

Which is applicable to all systems whether they are ideal or non-ideal.

It should be noted that if a solution exhibits ideal behavior then ‘a’ equals ‘x’, whereas ‘a’ does
not equal ‘x’ if deviations from such behavior are apparent. The ratio of activity/concentration is
termed the activity coefficient (f) and it provides a measure of the deviation from ideality.

Positive Deviation:

If the attractive forces between solute and solvent molecules are weaker than those exerted
between the solute molecules themselves or the solvent molecules themselves, then the
components will have little affinity for each other. The escaping tendency of the surface
molecules in such a system is increased compared to that of an ideal solution. In other words, pl,
p2 and P are greater than expected from Raoult's law, and the thermodynamic activities of the
components are greater than their mole fractions, i.e. a1 > xl and a2 > x2. This type of system is
said to show a positive deviation from Raoult's law, and the extent of the deviation increases as
the miscibility of the components decreases. For example, a mixture of alcohol and benzene
shows a smaller deviation than the less miscible mixture of water + diethyl ether, whereas the
virtually immiscible mixture of benzene + water exhibits a very large positive deviation.
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Fig. 2.3 Vapor pressure of a system showing positive deviation from Raoult's law

Negative Deviation:

Conversely, if the solute and the solvent have a strong mutual affinity that results in the
formation of a complex or compound, then a negative deviation from Raoult's law occurs. Thus,
pl, p2 and P are lower than expected and al < xl and a2 < x2. Examples of systems that show this
type of behavior include chloroform + acetone, pyridine + acetic acid and water + nitric acid.

Although most systems are non-ideal and deviate either positively or negatively from Raoult's
law, such deviations are small when a solution is dilute because the effects of a small amount of
solute on interactions between solvent molecules are minimal. Thus, dilute solutions tend to
exhibit ideal behaviour and the activities of their components approximate to their mole
fractions, i.e. a1 approximately equals xl and a2 approximately equals x2. Conversely, large
deviations may be observed when the concentration of a solution is high.
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Fig. 2.4 Vapor pressure of a system showing negative deviation from Raoult's law

Properties of solutions:

There are 3 main properties of solutions

 Colligative properties
 Additive properties
 Constitutive properties

Colligative properties:

Colligative properties depend mainly on the number of particles in a solution. The colligative
properties of solutions are osmotic pressure, vapor pressure lowering, freezing point depression,
and boiling point elevation. The values of the colligative properties are approximately the same
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for equal concentrations of different nonelectrolytes in solution regardless of the species or

chemical nature of the constituents. In considering the colligative properties of solid-in-liquid
solutions, it is assumed that the solute is nonvolatile and that the pressure of the vapor above the
solution is provided entirely by the solvent.

Additive properties:

Additive properties depend on the total contribution of the atoms in the molecule or on the sum
of the properties of the constituents in a solution. An example of an additive property of a
compound is the molecular weight, that is, the sum of the masses of the constituent atoms. The
masses of the components of a solution are also additive, the total mass of the solution being the
sum of the masses of the individual components.

Constitutive properties:

Constitutive properties depend on the arrangement and to a lesser extent on the number and kind
of atoms within a molecule. These properties give clues to the constitution of individual
compounds and groups of molecules in a system. Many physical properties may be partly
additive and partly constitutive. The refraction of light, electric properties, surface and interfacial
characteristics, and the solubility of drugs are at least in part constitutive and in part additive
properties

Colligative Properties:

When a non-volatile solute is dissolved in a solvent certain properties of the resultant solution
are largely independent of the nature of the solute and are determined by the concentration of
solute particles. These properties are known as colligative properties. In the case of a non-
electrolyte the solute particles will be molecules, but if the solute is an electrolyte then its degree
of dissociation will determine whether the particles will be ions only or a mixture of ions and un-
dissociated molecules.

Lowering of the Vapor Pressure:

When a nonvolatile solute is combined with a volatile solvent, the vapor above the solution is
provided solely by the solvent. The solute reduces the escaping tendency of the solvent, and, on
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the basis of Raoult's law, the vapor pressure of a solution containing a nonvolatile solute is
lowered proportional to the relative number. According to Raoult's law, the vapor pressure, p1,
of a solvent over a dilute solution is equal to the vapor pressure of the pure solvent, p1°, times
the mole fraction of solvent in the solution, X1. Because the solute under discussion here is
considered to be nonvolatile, the vapor pressure of the solvent, p1, is identical to the total
pressure of the solution, p. It is more convenient to express the vapor pressure of the solution in
terms of the concentration of the solute rather than the mole fraction of the solvent, and this may
be accomplished in the following way.

The sum of the mole fractions of the constituents in a solution is unity:

X1+X2=1 (2.8)

X1=1-X2 (2.8a)

p1°(X1) (2.8b)

p1°(1- X2) (2.8c)

p1°X2 (2.8d)

(2.9)

In equation (2.9), Δp = p1° - p is the lowering of the vapor pressure and Δp/p1° is the relative
vapor pressure lowering. The relative vapor pressure lowering depends only on the mole fraction
of the solute, X2, that is, on the number of solute particles in a definite volume of solution.
Therefore, the relative vapor pressure lowering is a colligative property.

Elevation of the Boiling Point:

The normal boiling point is the temperature at which the vapor pressure of the liquid becomes
equal to an external pressure of 760 mm Hg. A solution will boil at a higher temperature than
will the pure solvent. This is the colligative property called boiling point elevation. As shown in
Figure 2.5, the more of the solute that is dissolved, the greater is the effect. The boiling point of
a solution of a nonvolatile solute is higher than that of the pure solvent owing to the fact that the
solute lowers the vapor pressure of the solvent. This may be seen by referring to the curves in
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Figure 2.5. The vapor pressure curve for the solution lies below that of the pure solvent, and the
temperature of the solution must be elevated to a value above that of the solvent in order to reach
the normal boiling point. The elevation of the boiling point is shown in the figure as T -To =
ΔTb. The ratio of the elevation of the boiling point, ΔTb, to the vapor pressure lowering, Δp = p°
- p, at 100°C is approximately a constant at this temperature; it is written as;

X2 (2.10)

(2.11)

(2.12)

Where ΔTb is known as the boiling point elevation and Kb is called the molal elevation constant
or the ebullioscopic constant. It may be considered as the boiling point elevation for an ideal 1 m
solution. Stated another way, Kb is the ratio of the boiling point elevation to the molal
concentration in an extremely dilute solution in which the system is approximately ideal.

Fig. 2.5 Boiling point elevation of the solvent due to addition of a solute
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Depression of the Freezing Point:

The normal freezing point or melting point of a pure compound is the temperature at which the
solid and the liquid phases are in equilibrium under a pressure of 1 atm. Equilibrium here means
that the tendency for the solid to pass into the liquid state is the same as the tendency for the
reverse process to occur, because both the liquid and the solid have the same escaping tendency.
The value T0, shown in Figure 2.6, for water saturated with air at this pressure is arbitrarily
assigned a temperature of 0°C. The triple point of air-free water, at which solid, liquid, and vapor
are in equilibrium, lies at a pressure of 4.58 mm Hg and a temperature of 0.0098°C. It is not
identical with the ordinary freezing point of water at atmospheric pressure but is rather the
freezing point of water under the pressure of its own vapor. We shall use the triple point in the
following argument because the depression ΔTf here does not differ significantly from ΔTf at a
pressure of 1 atm. The two freezing point depressions referred to are illustrated in Figure 2.6.
The ΔTb of Figure 2.5 is also shown in the diagram.

If a solute is dissolved in the liquid at the triple point, the escaping tendency or vapor pressure of
the liquid solvent is lowered below that of the pure solid solvent. The temperature must drop to
reestablish equilibrium between the liquid and the solid. Because of this fact, the freezing point
of a solution is always lower than that of the pure solvent. It is assumed that the solvent freezes
out in the pure state rather than as a solid solution containing some of the solute. When such a
complication does arise, special calculations, not considered here, must be used. The more
concentrated the solution, the farther apart are the solvent and the solution curves in the diagram
(see Fig. 2.6) and the greater is the freezing point depression. Accordingly, a situation exists
analogous to that described for the boiling point elevation, and the freezing point depression is
proportional to the molal concentration of the solute. The equation is

(2.13)

ΔTf is the freezing point depression, and Kf is the molal depression constant or the cryoscopic
constant, which depends on the physical and chemical properties of the solvent. The freezing
point depression of a solvent is a function only of the number of particles in the solution, and for
this reason it is referred to as a colligative property. The depression of the freezing point, like the
boiling point elevation, is a direct result of the lowering of the vapor pressure of the solvent.
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Fig. 2.6 Depression of the freezing point of the solvent, water, by a solute

Osmotic Pressure:

If cobalt chloride is placed in a parchment sac and suspended in a beaker of water, the water
gradually becomes red as the solute diffuses throughout the vessel. In this process of diffusion,
both the solvent and the solute molecules migrate freely. On the other hand, if the solution is
confined in a membrane permeable only to the solvent molecules, the phenomenon known as
osmosis occurs, and the barrier that permits only the molecules of one of the components
(usually water) to pass through is known as a semipermeable membrane.
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A thistle tube over the wide opening of which is stretched a piece of untreated cellophane can be
used to demonstrate the principle, as shown in Figure 2.7. The tube is partly filled with a
concentrated solution of sucrose, and the apparatus is lowered into a beaker of water. The
passage of water through the semipermeable membrane into the solution eventually creates
enough pressure to drive the sugar solution up the tube until the hydrostatic pressure of the
column of liquid equals the pressure causing the water to pass through the membrane and enter
the thistle tube. When this occurs, the solution ceases to rise in the tube. Osmosis is therefore
defined as the passage of the solvent into a solution through a semipermeable membrane. This
process tends to equalize the escaping tendency of the solvent on both sides of the membrane.
Escaping tendency can be measured in terms of vapor pressure or the closely related colligative
property osmotic pressure. It should be evident that osmosis can also take place when a
concentrated solution is separated from a less concentrated solution by a semipermeable
membrane.

Fig. 2.7 Apparatus for demonstrating osmosis.

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Osmosis in some cases is believed to involve the passage of solvent through the membrane by a
distillation process or by dissolving in the material of the membrane in which the solute is
insoluble. In other cases, the membrane may act as a sieve, having a pore size sufficiently large
to allow passage of solvent but not of solute molecules. In either case, the phenomenon of
osmosis depends on the fact that the chemical potential (a thermodynamic expression of escaping
tendency) of a solvent molecule in solution is less than exists in the pure solvent. Solvent
therefore passes spontaneously into the solution until the chemical potentials of solvent and
solution are equal. The system is then at equilibrium.

It may be advantageous for the student to consider osmosis in terms of the following sequence of
events.

(a) The addition of a nonvolatile solute to the solvent forms a solution in which the vapor
pressure of the solvent is reduced.

(b) If pure solvent is now placed adjacent to the solution but separated from it by a
semipermeable membrane, solvent molecules will pass through the membrane into the solution
in an attempt to dilute out the solute and raise the vapor pressure back to its original value
(namely, that of the original solvent).

(c) The osmotic pressure that is set up as a result of this passage of solvent molecules can be
determined either by measuring the hydrostatic head appearing in the solution or by applying a
known pressure that just balances the osmotic pressure and prevents any net movement of
solvent molecules into the solution.

The osmotic pressure thus obtained is proportional to the reduction in vapor pressure brought
about by the concentration of solute present. Because this is a function of the molecular weight
of the solute, osmotic pressure is a colligative property and can be used to determine molecule
weights.
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Fig. 2.8 Osmotic pressure osmometer

An osmotic pressure osmometer (Fig. 2.8) is based on the same principle as the thistle tube
apparatus shown in Figure 2.7. Once equilibrium has been attained, the height of the solution in
the capillary tube on the solution side of the membrane is greater by the amount h than the height
in the capillary tube on the solvent (water) side.

The hydrostatic head, h, is related to the osmotic pressure through the expression osmotic
pressure π (atm) = Height h× Solution density ρ × Gravity acceleration.

The two tubes of large bore are for filling and discharging the liquids from the compartments of
the apparatus.
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Molecular Weight Determination:

Colligative properties can be used to calculate the molecular weights of nonelectrolytes present
as solutes. Thus, the lowering of the vapor pressure of a solution containing a nonvolatile solute
depends only on the mole fraction of the solute. This allows the molecular weight of the solute to
be calculated in the following manner.
Because the mole fraction of solvent, n1 = w1/M1, and the mole fraction of solute, n2 = w2/M2,
in which w1 and w2 are the weights of solvent and solute of molecular weights M1 and M2
respectively, equation (2.9) can be expressed as

(2.14)

In dilute solutions in which w2/M2 is negligible compared with w1/M1, the former term may be
omitted from the denominator, and the equation simplifies to;

(2.15)

The molecular weight of the solute M2 is obtained by rearranging equation (2.15) to

(2.16)

The molecular weight of a nonvolatile solute can similarly be determined from the boiling point
elevation of the solution. Knowing Kb, the molal elevation constant, for the solvent and
determining Tb, the boiling point elevation, one can calculate the molecular weight of a
nonelectrolyte.
(2.17)

The molecular weight of a nonvolatile solute can similarly be determined from the freezing point
depression of the solution.
(2.18)
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Example 2
Determination of the Molecular Weight of Sucrose by Boiling Point Elevation
A solution containing 10.0 g of sucrose dissolved in 100 g of water has a boiling point of 100.149°C. What is the
molecular weight of sucrose?
Solution:

Example 2.
Calculating Molecular Weight Using Freezing Point Depression
The freezing point depression of a solution of 2.000 g of 1,3-dinitrobenzene in 100.0 g of
benzene was determined by the equilibrium method and was found to be 0.6095°C. Calculate the
molecular weight of 1,3-dinitrobenzene.
Solution:

Factor affecting the solubility of solids in liquids:

1) Temperature:

The dissolution process is usually an endothermic one, i.e. Heat is normally absorbed when
dissolution occurs. In this type of system rise in temperature will lead to an increase in the
solubility of a solid with a positive heat of solution. Conversely, in the case of less commonly
occurring system that exhibit exothermic dissolution, then an increase in temperature will lead to
decrease in solubility.

Plot of Solubility versus Temperature referred to as solubility curves, are often used describe the
effect of temperature on a given system. Some examples are shown down in figure 2.9. Most of
the curves are continuous ones. However abrupt changes in slope may be observed with some
systems if a change in the nature of the dissolving solids occurs at a specific Transition
Temperature. For Example; Sodium sulphate exists as dehydrated Na2SO4.10H2O up to 32.5 oC
and its dissolution in water is an endothermic process. Its solubility will increase with rise of
temperature until 32.5 oC is reached. Above this temperature the solid is converted into
anhydrous form (Na2SO4) and the dissolution this compound is exothermic. The solubility
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therefore exhibits change from a positive to negative slope as the temperature exceeds the
transition value.

Fig. 2.9 Solubility curves of various substances in water

2) Molecular structure of solute:

It should be realized that even a small change in molecular structure of a compound can have a
marked effect on its solubility in a given liquid. For example, the introduction of a hydrophilic
hydroxyl group can produce a large improvement in water solubility, as evidenced by the more
than 100-fold difference in the solubilities of phenol and benzene. In addition, the conversion of
a weak acid to its sodium salt leads to a much greater degree of ionic dissociation of the
compound when it dissolves in water. The overall interaction between solute and solvent is
markedly increased and the solubility consequently rises. A specific example of this effect is
provided by a comparison of the aqueous solubilities of salicylic acid and its sodium salt, which
are 1:550 and 1:1, respectively. The reduction in aqueous solubility of a parent drug by its
esterification may also be cited as an example of the effects of changes in the chemical structure
of the solute. Such a reduction in solubility may provide a suitable method for:
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1. Masking the taste of a parent drug, e.g. chloramphenicol palmitate is used in paediatric
suspensions rather than the more soluble and very bitter chloramphenicol base;

2. Protecting the parent drug from excessive degradation in the gut, e.g. erythromycin propionate
is less soluble and consequently less readily degraded than erythromycin;

3. Increasing the ease of absorption of drugs from the gastrointestinal tract, e.g. erythromycin
propionate is also more readily absorbed than erythromycin.

3) Nature of solvent: co-solvents:

The importance of the nature of the solvent is in terms of the statement 'like dissolves like', and
in relation to solubility parameters. In addition, the point has been made that mixtures of solvents
may be employed. Such mixtures are often used in pharmaceutical practice to obtain aqueous-
based systems that contain solutes in excess of their solubilities in pure water. This is achieved
by using co-solvents such as ethanol or propylene glycol, which are miscible with water and
which act as better solvents for the solute in question. For example, the aqueous solubility of
metronidazole is about 100 mg in 10 mL has shown, however, that the solubility of this drug can
be increased exponentially by the incorporation of one or more water-miscible co-solvents, so
that a solution containing 500 mg in 10 mL and suitable for parenteral administration in the
treatment of anaerobic infection, can be obtained.

4) Crystal characteristics: polymorphism and solvation:

When the conditions under which crystallization is allowed to occur are varied, some substances
produce crystals in which the constituent molecules are aligned in different ways with respect to
one another in the lattice structure. These different crystalline forms of the same substance,
which are known as polymorphs, consequently possess different lattice energies, and this
difference is reflected by changes in other properties; for example, the polymorphic form with
the lowest free energy will be the most stable and possess the highest melting point. Other less
stable (or metastable) forms will tend to transform into the most stable one at rates that depend
on the energy differences between the metastable and the stable forms. The effect of
polymorphism on solubility is particularly important from a pharmaceutical point of view,
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because it provides a means of increasing the solubility of a crystalline material and hence its
rate of dissolution by using a metastable polymorph. Although the more soluble polymorphs are
metastable and will convert to the stable form the rate of such conversion is often slow enough
for the metastable form to be regarded as being sufficiently stable from a pharmaceutical point of
view. The degree of conversion should obviously be monitored during storage of the drug
product to ensure that its efficacy is not altered significantly. In addition, conversion to the less
soluble and most stable polymorph may contribute to the growth of crystals in suspension
formulations. Many drugs exhibit polymorphism, e.g. steroids, barbiturates and sulphonamides.
Examples of the importance of polymorphism with respect to the bioavailabilities of drugs and to
the occurrence of the absence of crystalline structure that is usually associated with a so-called
amorphous powder may also lead to an increase in the solubility of a drug compared to that of its
crystalline form.

In addition to the effect of polymorphism the lattice structures of crystalline materials may be
altered by the incorporation of molecules of the solvent from which crystallization occurred. The
resultant solids are called solvates; the phenomenon is referred to correctly as solvation and
sometimes incorrectly and confusingly as pseudopolymorphism. The alteration in crystal
structure that accompanies solvation shows that the solubilities of solvated and unsolvated
crystals will differ.

5) Particle Size:

The changes in interfacial freed energy that accompany the dissolution of particles varying sizes
cause the solubility of the substance to increase with decreasing particle size. The increase in
solubility will decrease particle size ceases when the particles have a very small radius (less than
1 micrometer) and any further decrease in size causes a decrease in solubility. It has been
postulated that this change arises from the presence of an electrical charge on the particles and
that the effect of this charge becomes more important as the size of the particles decreases.

6) pH:

Most of the drugs are either weak acid or weak bases and are poorly soluble in water. The
solubility of such drugs is markedly affected by a change in pH. If the pH of a solution of a
weakly acidic drug or its salt is reduced, the proportion of the unionized acid molecules in the
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solution increases. Since the unionized form is generally less soluble than ionized form, the
solubility of such drugs decreases with a decrease in the pH (amoxycillin, acetazolamide). On the
other hand, solubility of weakly basic drugs or their salts increases with a decrease in the pH
(atropine, allopurinol).

Common ion effect:

When slightly soluble electrolytes are dissolved to form saturated solutions, their solubility is
described by a special constant known as solubility product, Ksp. For a saturated solution of
sparingly soluble electrolyte AB in contact with undissolved electrolyte, the equilibrium may be
represented as follows:

AB A+ + B- (2.19)
(solid) (ions)
According to law of mass action, the equilibrium constant in terms of concentration is given by:
[ ][ ]
K= [ ]
(2.20)

Since the concentration of a solid may be regarded as being constant, the equation may be
written as:
Ksp= [ ][ ] (2.21)
Where Ksp is the solubility product of the compound AB.
If a compound that carries a common ion ( e.g A+) is added to the above system, there is a
momentary increase in the ionic product :
[ ][ ] (2.22)
In order to re-establish the equilibrium [A+][B-]=Ksp some of AB will precipitate out. The same
will be the effect if a compound containing the ion [B-] is added. Thus the addition of a
compound bearing a common ion reduces the solubility of sparingly soluble salt.

7) Effect of electrolytes on the solubility of non- electrolytes:

The solubility of non-electrolytes depends primarily on the formation of intermolecular bonds

(hydrogen bonds) between their molecules and those of water. Addition of an electrolyte having
more affinity towards water reduces the solubility of the non-electrolyte by competing for the
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aqueous solvent and breaking the intermolecular bonds between the non-electrolyte and water
8) Effect of non-electrolytes on the solubility of electrolytes:

The solubility of electrolytes in water primarily depends on dissociation of dissolved molecules

into ions. The ease with which the electrolytes dissociate depends on the dielectric constant of
the solvent which is infact the measure of the polar nature of the solvent. Addition of a water
soluble non-electrolyte such as alcohol to an aqueous solution of a sparingly soluble salt
decreases the solubility of the sparingly soluble electrolyte. This effect is due to the lowering of
the dielectric constant and this in turn then reduces the dissociation of the dissolved salt.
Factors affecting solubility of gases in liquids

 Temperature
 Pressure
 Presence of salts

1) Effect of Temperature:

Solubility of most gases decrease with a rise in temperature because of a greater tendency of the
gases to expand in comparison to the solvent. So gases in liquids are generally the pressurized
dosage forms and must be handled with great care while exposing them to temperature.

2) Effect of Pressure:

The pressure of a gas above the solution is important in gaseous solutions since this significantly
changes the solubility of the dissolved gas.The influence of pressure on solubility is expressed by
Henry’s law, which states that ―The mass of gas dissolved by a given volume of solvent at a
constant temperature is proportional to the pressure of the gas in equilibrium with the solution”.

If w is the mass of gas dissolved by unit volume of solvent at an equilibrium pressure, p, then
from Henry’s law

w = kp (2.23)

In general the solubility of gases in liquids increase with the increase in pressure and as the
pressure decreases the solubility also decreases resulting in the escape of gas molecules from the
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solution.
3) Effect of electrolytes and non- electrolytes:

Solubility of gases in a solvent is generally decreased or reduced by the addition of electrolytes

such as sodium chloride or non-electrolytes such as sugar. This is also called salting out. This is
due to more affinity and interaction between the solvent and the electrolyte or non- electrolyte
than between the solvent and the gas.

Partition coefficient:

If an excess of liquid or solid is added to a mixture of two immiscible liquids, it will distribute
itself between the two phases so that each becomes saturated. If the substance is added to the
immiscible solvents in an amount insufficient to saturate the solutions, it will still become
distributed between the two layers in a definite concentration ratio.

If C1 and C2 are the equilibrium concentrations of the substance in Solvent1 and Solvent2,
respectively, the equilibrium expression becomes

K=C1/C2 (2.24)

The equilibrium constant, K, is known as the distribution ratio, distribution coefficient, or

partition Coefficient

When boric acid is distributed between water and amyl alcohol at 25°C, the concentration in
water is found to be 0.0510 mole/liter and in amyl alcohol it is found to be 0.0155 mole/liter.
What is the distribution coefficient?

K= (2.25)

No convention has been established with regard to whether the concentration in the water phase
or that in the organic phase should be placed in the numerator. Therefore, the result can also be
expressed as;

K= (2.26)
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One should always specify which of these two ways the distribution constant is being expressed.
Applications of partition co-efficient:

 Pharmacokinetics:

In the context of pharmacokinetics (what the body does to a drug), the distribution coefficient
has a strong influence on ADME properties of the drug. Hence the hydrophobicity of a
compound (as measured by its distribution coefficient) is a major determinant of how drug-like it
is. More specifically, for a drug to be orally absorbed, it normally must first pass through lipid
bilayers in the intestinal epithelium (a process known as trans cellular transport). For efficient
transport, the drug must be hydrophobic enough to partition into the lipid bilayer, but not so
hydrophobic, that once it is in the bilayer, it will not partition out again. Likewise,
hydrophobicity plays a major role in determining where drugs are distributed within the body
after absorption and as a consequence in how rapidly they are metabolized and excreted.

 Extraction:

Distribution law is applied in analytical chemistry and inorganic chemistry to determine the
efficiency with which one solvent can extract a compound from a second solvent.

 Release of drug from certain dosage form:

Ointments are formulated in water immiscible bases. Release of medicaments from dosage form
like other factors also depends on partition coefficient of medicament between base and body
fluid

 Partition chromatography:

This technique is used to separate the component of a mixture. It depends upon the difference in
the distribution coefficient of the component between two liquids.

 Preservation of emulsions and creams:

In emulsions and creams microorganisms grow in aqueous phase and preservatives are added but
they are soluble both in oil and water. Therefore partition co-efficient of preservatives should be
noted to judge the total amount of preservatives to be used in these systems
References